Chronic kidney disease (CKD), affecting over 26 million Americans, frequently leads to kidney failure. More than 100,000 individuals develop end stage kidney disease (ESKD) annually and nearly 500,000 receive kidney transplants or are ongoing dialysis patients at an annual cost of $30 billion dollars. We and others showed that two APOL1 alleles comprising 2 missense variants in absolute linkage disequilibrium (G1 allele) and an in frame 6 base pair deletion (G2 allele) on an opposing chromosome were responsible for the increased risk of chronic kidney disease in black Americans. APOL1 provides protection against infection with Trypanosoma brucei brucei. The APOL1 risk alleles emerged recently in sub-Saharan Africa, but are found in other regions of the world as a result of the African Diaspora. The combined frequencies of G1 and G2 alleles are approximately 35% in African Americans, with 13% of African Americans and up to 25% of West African carrying high risk genotypes. These alleles explain nearly all the excess risk of kidney disease in African Americans, thus providing a genetic basis for a major global health disparity. We have now extended our research to investigate the independent and interactive effects of sickle cell trait on cardiovascular and kidney diseases. The role of APOL1 risk variants in cardiovascular disease is conflicted with some studies showing a protective association and others reporting a susceptible or no association. We are investigating the role of APOL1 in cardiovascular disease in large well-powered community- based studies to separate the mediating effects of underlying co-morbidities (CKD and diabetes) from APOL1 associations. Accomplishments: 1) APOL1 coding variants and risk of heart failure. Compared to whites, stroke and heart failure is more common among African American women as they age. We found that among post-menopausal women enrolled in the Women's' Health Initiative, APOL1 was not associated with increased risk of cardiovascular diseases; however, APOL1 is associated with heart failure with preserved injection fraction, which is more common among African Americans and possibly mediated by underlying chronic kidney disease (Franceshini et al., JAMA Cardiology, 2018). 2) Cardiovascular disease, including ischemic stroke and myocardial infarction, is more common among African Americans. We evaluated nearly 10,000 African Americans enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) for APOL1 risk variants and determined that carriers of two APOL1 risk alleles were at a 2.3 -fold higher than for non-carriers for composite cardiovascular events; however, these associations were driven ischemic stroke. Carriers of high risk APOL1 genotypes were over 5-fold more likely to experience small vessel ischemic stroke compared to those with low-risk genotypes who did not have chronic kidney disease or diabetes, indicating that APOL1 is a direct contributor to these outcomes and not a moderator acting through underlying co-morbidities (Gutierrez et al., Circ Genom Precis Med, 2018). These results have public health policy implications for genetic counseling of high risk carriers. 4) Sickle cell trait (SCT) has long been considered a benign; however, its role has not been analyzed in large-scale studies or by meta-analysis. Sickle cell trait, which is carried by 7% of African Americans, does not appear to be a risk factor for stroke (Hyacinth et al., JAMA Neurol, 2018). 5) Black living kidney donors are at higher risk of developing kidney disease than white donors. Because APOL1 high risk status (carriage of two risk alleles) is such a strong risk factor for chronic kidney disease, we asked if APOL1 genotype of living kidney donors might affect the donors' health following nephrectomy for kidney donation. We studied 136 living donors with APOL1 genotyping and found that pre-donation characteristics were similar between those having 2 APOL1 risk alleles (high-risk status) and those with one or no risk alleles (low-risk status). At a median time of 12 years post-donation, APOL1 high-risk donors had lower estimated glomerular filtration (eGFR) rates and more rapid loss of kidney function compared to those with APOL1 low-risk status. This study suggests that donors carrying two risk alleles might be at greater risk for greater decline in kidney function and kidney failure, but larger studies are required to validate this finding (Doshi et al., Am J Soc Nephrol, 2018). We are now extending our studies to donation between recipient donor pairs with HIV infection to determine if APOL1 status contributes to kidney survival in living donors and their kidney recipients in the HOPE clinical trial. 6) Preeclampsia characterized by proteinuria and hypertension is a major complication of pregnancy resulting in fetal and maternal morbidity and mortality. In two cohorts, we found that carriage of APOL1 high risk genotypes by the fetus, but not the mother, increases the risk of preeclampsia by two-fold (Reidy et al., AJHJ, 2018). We are now investigating genetic modifiers of APOL1-associated preeclampsia and RNA transcriptional profiles in APOL1 high and low risk placentas from mothers with and without preeclampsia to better understand the pathogenic mechanisms and perturbed pathways. In order to study both US-born and foreign born mother-fetal pairs, we are collaborating with the large longitudinal Boston Birth Cohort. In preliminary studies we found fetal APOL1 high-risk status was associated with a 6-fold increased risk of maternal preeclampsia in US-born African American mothers, but the risk of preeclampsia was completely attenuated in mothers born in Haiti. We have hypothesized that genetic or environmental (such as maternal folic acid levels) differing between the two groups may be affecting penetrance. We are investigating gene X environment (Folic acid levels) interactions in this cohort of over 3000 mother-fetal pairs as well as the long term consequences of preeclampsia and APOL1 status on hypertension and renal function in offspring of preeclampsic births. 7) With Bench to Bedside funding we are utilizing single cell transcriptomics of urinary cells (podocytes and other cells) to identify pathways and gene expression differences between patients with APOL1-associated focal segmental glomerulosclerosis (FSGS) and primary FSGS as well as between steroid responsive and steroid responsive FSGS. 8) Individuals with APOL1 high-risk (HR) genotypes are at a higher for kidney disease and this risk increases in those with HIV infection. In the Renal Risk Reduction R3 clinical trial, the efficacy of blocking the renin angiotensin aldosterone system with angiotensin-converting enzyme inhibitors (ACEi) is being tested in a randomized clinical trial enrolling 280 participants living in Nigeria with microalbuminuria, an early marker of renal injury. The goals of the study to screen 2600 HIV-positive adults who have received ART to (1) determine the prevalence of APOL1 risk variants and assess whether APOL1 HR status correlates with prevalent albuminuria, estimated glomerular filtration rate (eGFR), and/or prevalent CKD; (2) assess, via a randomized, placebo-controlled trial (RCT) in a subset of these participants with microalbuminura (n = 280) whether addition of the ACEi, lisinopril, compared to standard of care, significantly reduces the incidence or progression of albuminuria; and (3) determine whether the APOL1 HR genotype is associated with worse kidney outcomes (i.e. eGFR slope or regression of albuminuria) among participants in the RCT (Aliyu et al. Trials, 2019). Our unexpected preliminary finding was that 40% of the screened participants have microalbuminuria, an early marker for renal injury, and we are now investigating the contribution of genetic variants to this remarkable result.